1. Technical Field of the Invention
The invention relates to new deuterated morphine derivatives of general formula (I), and stereoisomers including enantiomers, diastereomers, racemic mixtures, mixtures of enantiomers or combinations thereof, as well as polymorphs, tautomers, solvates, salts, esters and prodrugs thereof, furthermore to a process for the preparation thereof, and to pharmaceutical compositions comprising them.
2. Description of the Prior Art
Morphine, member of the opiates, is the most commonly used narcotic analgesic agent for the treatment of severe chronic and acute pain. An example of chronic pain is the pain which occurs in cancer. An example of acute pain is the pain which may occur after operations. Morphine is a powerful analgesic routinely used to reduce pain in humans. For example, surgery patients are typically instructed to take 5 to 10 mg of morphine per person to alleviate pain caused by the surgical procedure. In some cases, patients suffering from extreme pain (e.g., burn victims or cancer patients) are instructed to take higher doses of morphine. For moderate to severe pain, the optimal intramuscular dosage is considered to be 10 mg per 70 kg body weight every four hours. The typical dose range is from 5 to 20 mg every four hours, depending on the severity of the pain. The oral dose range is between 8 and 20 mg, but orally administered morphine has substantially less analgesic potency. The intravenous route is used primarily for severe post-operative pain or in emergency. In such cases, the dose range is between 4 and 10 mg, and the analgesic effect ensues almost immediately (Hardman, J. G.; Limbird, L. E.; Molinoff, P. B.; Ruddon, R. W. Goodman Gilman, A. Goodman and Gilman's The Pharmacological Basis of Therapeutics, Ninth Edition, 1996).
Dihydromorphine is slightly stronger than morphine as an analgesic with a similar side effect profile. Dihydromorphine may have better bioavailability after oral administration than morphine. The onset of action is more rapid than that of morphine and it also tends to have a longer duration of action, generally 4-7 hours. At the present time, dihydromorphine is most commonly used in Japan, and various European and Asian countries. A United Nations report in 1993 stated increases in use of dihydromorphine in some Central European countries, and, later, WHO and EU reports show the same, although distinction is not made between use of dihydromorphine (Paramorfan) as an analgesic product, and the use of dihydromorphine in the manufacture of other drugs. The latter is also the case in the United States, where it is seen exclusively as an intermediate in the manufacture of dihydrocodeine as well as in some methods of manufacture of hydrocodone, hydromorphone, and related drugs (http://en.wikipedia.org/wiki/Dihdromorphine).
The opiates used up until now for treating pain are indeed highly effective but have a number of unpleasant and/or undesirable side effects, e.g. a short duration of activity, respiratory depression, nausea, constipation, diuresis and euphoria and they are also addictive. The property of opioids to induce euphoria is considered the basis for their potential to be abused. Moreover, the very effective and rapidly acting diacetyl derivative of morphine (heroin) cannot have any clinical applications because of abuse potential.
The ambivalent nature of said substances, i.e. their potential to offer medical benefit but also to promote abuse, have been known for a long time (Thesis of Dr. Jung S.; dgra.de/studiengang/pdf/master_jung_s.pdf and the references cited therein). As a consequence an international control system was established already at the beginning of the last century to prevent the abuse of these substances and to limit their licit use to purely medical and scientific purposes (Bayer I., Ghodse H.; “Evolution of International Drug Control, 1945-1995”, Bulletin on Narcotics Volume LI, United Nation Office on Drugs and Crime, 1999).
Despite tight international control, diversion and abuse of psychoactive substances still constitute major public health and social problems in the majority of countries worldwide. Interestingly, in the U.S., which is the world's largest single market for illicit drugs (2004 INCB report: E/INCB/2004/1), abuse of prescription medicines, especially of those containing morphine, oxycodone, hydrocodone, codeine and other opioids, has become a major problem.
According to the U.S. National institute of Drug Abuse (NIDA, InfoFacts 2005), opioid abuse and dependence may contribute to other serious health problems including the spread of HIV or hepatitis (because of risky behavior like needle sharing and unsafe sex), adverse cardiovascular effects, ranging from abnormal heart rate to heart attacks, liver damage. Opioid abuse may also be associated with psychiatric illness such as depression and generalized anxiety disorder [Hahesy et al; “Temporal association between childhood psychopathy and substance use disorders: Findings from a sample of adults with alcohol or opioid dependency”, Psychiatry Res. 109(3): 245-253. 2002], and cognitive impairment (Ornstein et al.; “Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers”, Neuropsychopharmacology, 23; 113-126, 2000). In addition to these adverse medical consequences, opioid abuse and dependence is also known to contribute to severe social problems such as individual, family and community disintegration.
While it is important to make efficacious medicines containing psychoactive substances available to patients who need them, it is at the same time imperative to judge their potential for abuse, i.e. their “abuse liability” and, if necessary, take special precautions to prevent abuse and diversion of these products. A sensible balance between access to useful drugs and protecting the public from the consequences and dangers of ready access to substances of abuse must be found (Thesis of Dr. Jung, S.; dgra.de/studiengang/pdf/master_jung_s.pdf and the references cited therein). Moreover, there is a big need for novel and more potent opioid derivatives. (Corbett, A. D.; Henderson, G. McKnight, A. T.; Paterson, S. J.; Brit. J. Pharm. 147, S153-S162, 2006.) For decades long only one novel opioid derivative, the tapentadol has been introduced to therapeutic use. (Hartrick, C.; van Hove, I.; Stegmann, J. U.; Oh, C.; Upmalis, D.; Clinical Therapeutics 31, 260-271, 2009.)
In the U.S. alone, approximately 100 million people suffer from acute and chronic pain. Because of this potentially large market, pharmaceutical industry is in continuous search for new substances to treat neurological and psychiatric disorders.
During the last 2 decades, there has been a dramatic increase in the use of strong opioids for chronic non-cancer pain. This increase has been accompanied by a steep increase in abuse, misuse, and both fatal and non-fatal overdoses involving prescription opioids. The situation is already alarming in the US. Prescription opioid-related harm is a complex, multifactorial issue that requires a multifaceted solution. In this respect, formulations of opioid analgesics designed to resist or deter abuse may be a useful component of a comprehensive opioid risk minimization program. Such formulations have or are being developed.
Abuse-resistant opioids include those that use some kind of physical barrier to prevent tampering with the formulation. For example the patent application EP 1986650 A1 discloses special dosage forms used for the prevention of the illicit use of opioid agonist formulations. Moreover, it has been stated that drug formulations present significant barriers to tampering reduce, but do not totally eliminate misuse (Cone, E. J.; Drug Alc.l Dep., S31-S39, 2006).
Abuse-deterrent opioids are not necessarily resistant to tampering, but contain substances that are designed to make the formulation less attractive to abusers. Two products intended to deter abuse were reviewed by the US Food and Drug Administration (FDA) (Bannwarth, B. Drugs, 72, 1713-1723, 2012).
The first composition (Embeda®) consists of morphine for extended-release with sequestered naltrexone, an opioid antagonist that is released if the tablet is compromised by chewing or crushing. Although Embeda® exhibited abuse-deterrent features, its label warns that it can be abused in a manner similar to other opioid agonists. Furthermore, tampering with Embeda® will result in the release of naltrexone, which may precipitate withdrawal in opioid-tolerant individuals. In March 2011, all dosage forms of Embeda® were recalled because the product failed to meet routine stability standards, and its return date to the market is currently unknown (http://www.reuters.com/article/2011/03/16/us-pfizer-recallidUSTRE72FA3Q20110316).
The second product (Acurox®) was intended to be both tamper resistant and abuse deterrent. It consisted of an immediate-release oxycodone tablet with subtherapeutic niacin as an aversive agent and used a gel-forming ingredient designed to inhibit inhalation and prevent extraction of the drug for injection. The new drug application for Acurox® was rejected in 2010 by the FDA because of concerns about the potential abuse-deterrent benefits of niacin (Mastropietro D J, Omidian H, Drug Dev. Ind. Pharm. Epub 2012 Apr. 26).
While acknowledging that no formulation can be expected to deter all types of opioid-abusive behaviors and no product is likely to be abuse proof in the hands of clear and determined abusers, for the reductions in abuse new products would provide an incremental step towards safer prescription of opioids (Drugs, 72, 1713-1723. 2012). Consequently, there is a continuous need for safe and efficacious drugs.
Thus, the principal aim of the present invention is the provision of compounds with higher receptor binding affinity resulting in improved pharmacological properties for example in higher analgesic and antitussive activity, with longer duration of action and reduced adverse effects through the administration of lower doses, and additionally with a reduced risk of the possibility of drug abuse.
The present invention provides novel deuterated morphine derivatives of general formula (I) with high and selective μ-opioid receptor activity. It has been surprisingly and unexpectedly found that morphine derivatives deuterated in 7,8-position of the morphine ring show high opioid receptor binding activity which is selective towards the μ-receptor whereby they are useful for example in the management of pain or may be used as antitussive drugs. The analgesic effect of compounds of invention is higher and of prolonged duration when compared to that of the corresponding hydrogenated derivatives, thus permitting the administration of lower dosages, resulting in reduced adverse effects. Moreover because of the incorporated deuterium atoms in the morphine ring itself in positions not attained by the first steps of the metabolic pathway the presence of the compounds or that of their metabolites can be followed up easily in a patient leading to higher safety in application and drug abuse cases may be discovered and prevented.
The deuterium is a naturally occurring, stable, non-radioactive hydrogen isotope. The hydrogen atom contains one electron, and one proton in the nucleus. Consequently the mass of the hydrogen atom is one AMU. The deuterium atom contains one electron and one proton and one neutron in the nucleus. Consequently the mass of the deuterium atom is two AMU. Natural occurrence of deuterium atom comparing to the hydrogen atom is 1:6600 (Marter, W. L.; Hayes, D. W.; Jones, D. W. Encyclopedia of Chemical Processing and Design, Issue 15, McKetta, J. C.; Cunningham, W. A. Eds, Marcel Dekker, 1982.). The toxicity of deuterium is very low. The human body tolerates very high heavy water content, for example a body fluid with a deuterium content of 15-23% showed no harmful effect (Blagojevic, N.; Storr, G.; Allen, J. B.; Advanced Medical Publishing, Madison Wis., 1994).
Comparing a deuterium containing molecule with the corresponding unlabeled one, many properties (such as: molecule shape, surface, etc.) of both are identical, due to the same electron cloud around the molecules, the incorporation of deuterium atom does not influence the molecular shape. For example the perdeuterated variant of arginaze-I enzyme showed the same behavior in biological assays and X-ray investigation compared to the native hydrogenated one (Di Costanzo, L.; Moulin, M.; Haertlein, M.; Meilleur, F.; Christianson, D. W.; Arch. Biochem. Biophys, 465, 82, 2007).
However, the physical properties of deuterated derivatives may be different from that of the hydrogen containing ones. Due to the change of hydrogen for deuterium the hydrophobicity of the molecule can decrease or if the deuteration place is next to an ionizable functional group, the pKa can alter as well. Consequently, the receptor binding selectivity or affinity of a deuterated drug molecule may change compared to the hydrogen containing one. One possible explanation of this effect is that the C-D bond is 6-10 times stronger, than the C—H bond. Accordingly the C-D bond is less polarizable, cleavable and reactive. This phenomenon is called kinetic isotope effect (KIE) (Bell R. P.; Chem. Soc. Rev. 3, 513, 1974). Consequently the KIE can influence the binding of drug molecules to their receptor or can alter the metabolism of deuterium labeled drugs if the deuteration point is next to the metabolization place.
On the other hand in real biological systems, many rival processes may alter the action of KIE (Fisher, M. B.; Henne, K. R.; Boer; J. Curr. Opin. Drug. Discov. Devel. 9, 110, 2006). There are three ways for said alteration: (i) slower metabolization (Kushner, D. J.; Baker, A.; Dunstall, T. G.; Can. J Physiol. Pharmacol., 77, 79, 1999); (ii) appearance of alternative metabolizing ways (Kushner, D. J.; Baker, A.; Dunstall, T. G.; Can. J Physiol. Pharmacol. 77, 79, 1999, and Mutlib, A. E.; Gerson, R. J.; Meunier, P. C.; Toxicol. Appl. Pharmacol., 169, 102, 2000) and (iii) and in some rare cases, the metabolism can be accelerated as well (only one in vitro experiment) (http://www.concertpharma.com/about/documents/IPT32ConcertPharma.pdf).
Slower metabolism can appear in two different forms as well. In the case of slower metabolism in the systemic blood stream the half-life of the molecule will be increased, leading to a broader AUC curve, consequently the duration of the effect, i.e. the time interval between two dosages, will be longer. The slower metabolism in the liver or in the intestinal wall (before the systemic blood stream) will lead to higher cmax values. Consequently lower dosages can be applied.
In the case of alternative metabolizing ways, new active metabolites may appear. This phenomenon can result in a protracted effect and shorter time intervals between two dosages (Mutlib, A. E.; Gerson, R. J.; Meunier, P. C.; Toxicol. Appl. Pharmacol. 169, 102, 2000).
Deuterium containing samples have been widely used as internal standards in pharmacokinetic investigation, but there are only few examples of studying the pharmacodynamics of deuterated drug molecules. Deuteration usually changes one or more pharmacodynamic properties of the compound, for example absorption, distribution, metabolism and excretion properties. For example amphetamines are more readily transported into the brain in deuterated form (Wenzel, M., Erhöhte Gehirn-affinität von 131J-markierten N-(Alkyl)-amphetaminen nach Deuterierung. J. Labelled Compd. Radiopharm., 27: 1143-1155, 1989); halogenated anaesthetics, such as selvoflurane, when deuterated are no longer oxidized to toxic forms within the body (Baker M T, Ronnenberg, Jr. W C, Ruzicka J A, Chiang C-K, Tinker J H.; Inhibitory effects of deuterium substitution on the metabolism of sevoflurane by the rat. Drug Metabolism and Disposition 21: 1170-1171. 1993). The metabolism of the deuterated fludalanin occurred in an alternative way (Kahan, F.; Chem. Engin. News., 87, 2009), but in some patients with metabolic disorders the benefit of the altered metabolism could not be exploited. Harmful drug interactions caused by a paroxetin metabolite may perhaps be avoided by a deuterated paroxetin derivative (CTP-347) metabolizing in a different way (http://www.concertpharma.com/).
A deuterated morphinan compound bearing deuterated substituent in the side chains of the morphine ring i.e. N-d3-methyl-3-d3-methoxy-mophinan, is reported in the patent application EP 2152709 A1 to demonstrate a longer clearance and produce a higher plasma exposure level hours post-dosing as compared to their non-deuterated form. Since the N- and O-demethylated metabolites of the morphinan formed via multiple catalytic steps are responsible for its biological action an altered metabolic pathway due to said deuterated derivative lead to the beneficial effect in this case.